Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II

• Published in: PloS one Vol. 7; no. 5; p. e35144
• Main Authors: Ma, Feifei, Li, Yulin, Jia, Lixin, Han, Yalei, Cheng, Jizhong, Li, Huihua, Qi, Yongfen, Du, Jie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-05-2012; Public Library of Science (PLoS)
• Subjects: Actin; Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Animals; Antibodies; Biology; Cardiac muscle; Cardiomyocytes; Cardiomyopathy; Cardiovascular disease; Cardiovascular system; Cell activation; Collagen (type I); Collagen - biosynthesis; Cytokines; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosis; Gene expression; Gene Expression Regulation - drug effects; Growth factors; Heart; Heart diseases; Heart failure; Hospitals; Hypertension; Immunohistochemistry; Immunology; Immunoregulation; Inflammation; Interleukin 6; Interleukin-6 - biosynthesis; Interleukin-6 - deficiency; Interleukin-6 - genetics; Kinases; Laboratory animals; Macrophages; Macrophages - metabolism; Male; Medicine; Mice; Mice, Inbred C57BL; Muscles; Myocardium - metabolism; Myocardium - pathology; Oxidative stress; Phosphorylation; Phosphorylation - drug effects; Rodents; Sepsis; Smad protein; Smad3 protein; Smad3 Protein - metabolism; Smooth muscle; Staining; Transforming growth factor; Transforming Growth Factor beta1 - biosynthesis; Transforming Growth Factor beta1 - metabolism; Transforming growth factor- beta; Transforming growth factor- beta 1; Transforming growth factor-b1; Beijing China; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035144

Interleukin-6 (IL-6) is an important cytokine participating in multiple biologic activities in immune regulation and inflammation. IL-6 has been associated with cardiovascular remodeling. However, the mechanism of IL-6 in hypertensive cardiac fibrosis is still unclear. Angiotensin II (Ang II) infusion in mice increased IL-6 expression in the heart. IL-6 knockout (IL-6-/-) reduced Ang II-induced cardiac fibrosis: 1) Masson trichrome staining showed that Ang II infusion significantly increased fibrotic areas of the wild-type mouse heart, which was greatly suppressed in IL-6-/- mice and 2) immunohistochemistry staining showed decreased expression of α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and collagen I in IL-6-/- mouse heart. The baseline mRNA expression of IL-6 in cardiac fibroblasts was low and was absent in cardiomyocytes or macrophages; however, co-culture of cardiac fibroblasts with macrophages significantly increased IL-6 production and expression of α-SMA and collagen I in fibroblasts. Moreover, TGF-β1 expression and phosphorylation of TGF-β downstream signal Smad3 was stimulated by co-culture of macrophages with cardiac fibroblasts, while IL-6 neutralizing antibody decreased TGF-β1 expression and Smad3 phosphorylation in co-culture of macrophage and fibroblast. Taken together, our results indicate that macrophages stimulate cardiac fibroblasts to produce IL-6, which leads to TGF-β1 production and Smad3 phosphorylation in cardiac fibroblasts and thus stimulates cardiac fibrosis.